BIOPESTICIDES REGISTRATION ACTION DOCUMENT

Bacteriophage of Clavibacter michiganensis subspecies michiganensis

Pesticide Chemical (PC) Code: 228983

U.S. Environmental Protection Agency Office of Pesticide Programs Biopesticides and Pollution Prevention Division

August 25, 2011Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 2 of 22 Biopesticides Registration Action Document

TABLE OF CONTENTS

I. EXECUTIVE SUMMARY

................................ ................................ .............................. 4

II. ACTIVE INGREDIENT OV ERVIEW

................................ ................................ ........... 6

A. Application for Pesticide Registration

................................ ................................ ................................ .... 7

B. North American Free Trade Agreement Joint Review

................................ ................................ ......... 7

C. Food Tolerance Exemption

................................ ................................ ................................ ...................... 7

IV. RISK ASSESSMENT

................................ ................................ ................................ ....... 7

A. Product Analysis Assessment (40 CFR § 158.2120)

................................ ................................ ............... 8

B. Human Health Assessment (40 CFR § 158.2140)

................................ ................................ ................... 8

C. Environmental Assessment (40 CFR § 158.2150)

................................ ................................ ................ 13

V. ENVIRONMENTAL JUSTIC E

................................ ................................ .................... 14

VI. RISK MANAGEMENT DECI SION

................................ ................................ ............. 14

VI I. ACTIONS REQUIRED BY THE REGISTRANT

................................ ...................... 15

A. Final Printed Labeling

................................ ................................ ................................ ........................... 15

B. Terms of Registration

................................ ................................ ................................ ............................. 15

C. Reporting of Adverse Effects and Hypersensitivity Incidents

................................ ............................ 16

VIII. GLOSSARY OF A CRONYMS AND ABBREVIA TIONS

................................ ........... 17

IX. BIBLIOGRAPHY

................................ ................................ ................................ ........... 18

A. Studies Submitted to Support the AgriPhage CMM Pesticide Product Registration

...................... 18

B. Environmental Protection Agency and Pest Management Regulatory Agency Risk Assessment

Memoranda

................................ ................................ ................................ ................................ .................. 18

APPENDIX A. MICROBIA L PESTICIDES DATA RE QUIREMENTS

............................. 20

APPENDIX B. PESTICID E PRODUCTS

................................ ................................ ................ 22Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 3 of 22 Biopesticides Registration Action Document

BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM

Office of Pesticide Programs (OPP) Biopesticides and Pollution Prevention Division

Microbial Pesticides Branch

Science Reviews

Joel V. Gagliardi , Ph.D. Product Analysis, Environmental Effects,

Human Health U.S. Environmental Protection Agency

Jonas Ptasinski Product Analysis, Environmental Effects

, Human Health Health Canada Pest Management Regulatory Agency

Regulations

Sheryl K. Reilly, Ph.D. Chief, Microbial Pesticides Branch U.S. Environmental Protection Agency

Denise Greenway Regulatory Action Leader

Anna Gross Regulatory Actio n Leader Matthew Thompson Regulatory Action LeaderBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 4 of 22 Biopesticides Registration Action Document

I

. EXECUTIVE SUMMARY

In March 2009

, OmniLytics, Inc

. submitted a n application for an end

- use pesticide product, AgriPhage CMM (EPA File Symbol 67986

- A) , to both the United States Environmental Protection Agency (EPA) and the Health Canada Pest Management Regulatory Agency (PMRA)

, and requested a North American Free Trade Agreement (NAFTA) Joint Review of its application. AgriPhage CMM contains a new active ingredient, bacteriophage of Clavibacter michiganensis subsp. michiganensis , and is proposed for use as a bactericide on tomato plants to

control bacterial canker disease. AgriPhage CMM is composed of individually derived mixtures

of a library of bacteriophage s with specific activ ity for lysing Clavibacter michiganensis subsp. michiganensis pathogenic to tomato es

.

Bacteriophage s are viruses that only infect specific bacteria. Clinical uses encompass all manner of administration from injection/ intravenous and surgical wound applica tions

, to topical and ingestible preparations . They are also used to test normal and variously impaired human immune system function s . There have been no reports of adverse effects from such administrations of bacteriophage in the published literature or in scientifically controlled case studies. Literature cited by the applicant demonstrated that bacteriophage s are present in high numbers in the

environment

, including non

- polluted waters up to 10 10 PFU/L and up to 10 5 PFU/L in treated drinking water. Bac teriophage presence has been r eported in foods and feeds ranging from 10

- 10 5 PFU/100 g in meats and up to 10 7 PFU/100 g in cheese, without any known harmful effects after consumption. Bacteriophage s are common and abundant in soils and in a wide range of

p lant materials.

The main risk issue associated with the use of bacteriophage as a pesticide is whether any or all of

the bacteriophage s in the library and the host bacteri um produce toxins or pathogenicity factors.

Peer

- reviewed literature

, analysis of the host strain

, and the bacteriophage properties submitted by the applicant show ed the host strains do not produce toxic or pathogenic factors

. H ost range testing

verifie d that the bacterio phage cannot cross

- infect bacteri a that may carry toxins.

EPA a nd PMRA scientists have reviewed product analysis, toxicology, and nontarget organism

data and information submitted to support the registration of the bacteriophage of Clavibacter michiganensis subsp. michiganensis pesticide product. P roduct analysis data requirements for bacteriophage of Clavibacter michiganensis subsp. michiganensis , including product chemistry and composition, analysis of samples, and physical and chemical characteri stics, were fulfilled by acceptable guideline studi es. The applicant included a thorough scientific literature review

, and requested t he EPA to waive the data requirements for mammalian and nontarget organism toxicology, pathogenicity, infectivity and irritation testing for bacteriophage of Clavibacter

mic higanensis subsp. m ichiganensis , based upon its biological proper ties and narrow host range. EPA accepted the waivers of these data requirements, because the submitted literature demonstrated that bacteriophages are unable to infect eukaryotic cells. It i s reasonable, therefore, to expect that they are not capable of infecting eukaryotic organisms, including humans and nontarget animals and plant species , and no bacteriophage infections of eukaryotic organisms have been reported . Nontarget bacteria are als o unlikely to be adversely affected, due to the narrow host range of the bacteriophage.

E PA has made a preliminary conclusion that there is a reasonable certainty that no harm will result to the United States population, including infants and children, from aggregate exposure to residues

of bacteriophage of Clavibacter michiganensis subsp. michiganensis

. Based on the narrow hostBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 5 of 22 Biopesticides Registration Action Document

range of bacteriophage of Clavibacter michiganensis subsp. michiganensis to certain bacterial species and the in ability of bac teriophage in general to infect eukaryotic cells, bacteriophage of Clavibacter michiganensis subsp. michiganensis are not expected to pose any singular or

cumulative risks to humans, including infants and children, or to other mammals through exposure

in t he food supply, from drinking or surface waters, or through other non

- dietary exposures. In

addition , nonoccupational exposure is considered unlikely for bacteriophage of Clavibacter michiganensis subsp. michiganensis as all currently proposed uses occur i n distinctly agricultu ral or commercial settings; the re are no proposed uses for residential areas.

Despite the low toxicological profile of bacteriophage of bacteriophage of Clavibacter michiganensis subsp. michiganensis , baseline personal protective equipment (PPE) is required for handlers that may be exposed to the active ingredient, due to their occupation, for prolonged periods or numerous times . Handlers working with bacteriophage of Clavibacter michiganensis subsp. michiganensis in occupational a nd agricultural settings are directed to wear a long

- sleeved shirt, long pants, socks, shoes, and waterproof gloves; a dust/mist filtering respirator meeting National Institute for Occupational Safety and Health (NIOSH) standards of at least N

- 95, R

- 95,

or P

- 95 is required for workers when repeated inhalation exposures occur.

The submitted data and other information fulfill ed the curr ent data requirements and were adequate f or risk assessment purposes. EPA has concluded that the proposed use of bacterioph age of Clavibacter michiganensis subsp. m i chiganensis meets the safety standards for registration under Section 3(c)(5) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)

.

On October 1, 2009, EPA announced a new policy to provide a more meaningful opportunity for the public to participate in major registration decisions before they occur. According to this policy, EPA intends to provide a public comment period prior to makin g a registration decision for, at minimum, the following types of applications: new active ingredients; first food uses; first outdoor uses; first residential uses; or any other registration actions for which EPA believes there may be significant public in terest.

Consistent with the policy of making registration actions more transparent, the proposed

pe sticide product containing bacteriophage of Clavibacter michiganensis subsp. michiganensis

, a new active ingredient, is subject to a 30

- day comment period . In addition to containing a new active ingredient, the registration of this product would result in both the first outdoor use and

first food use for bacteriophage of Clavibacter michiganensis subsp. michiganensis

. The docket

identification number

, assoc iated with these registration actions and accessed through either http://www.regulations.gov/ or http://www.epa.gov/pesticides/regulating/registration

- status.html

, is EPA

- HQ

- OPP

- 20 09

- 0539

. The following documents are available for comment in EPA

- HQ

OPP

- 2009

- 0539 : (1) proposed bacteriophage of Clavibacter michiganensis subsp. michiganensis Biopesticide s Registration Action Document (BRAD) ; (2) environmental risk assessment for bacteriophage of Clavibacter michiganensis subsp. michiganensis ; and (3) proposed product

label for the end

- use pesticide product, AgriPhage CMM (EPA File Symbol 67986

- A ). While a final decision on registration is contingent upon review and consideration of public comments, EPA presently believes t hat, based upon the risk assessment and informat ion submitted in support of AgriPhage CMM , it is in the best interest of the public and the environment to issue this registration

. The basis for this preliminary decision can be found in the risk assessment for bacteriophage of Clavibacter michiganensis subsp. michiganensis , which is characterized throughout this BRAD

.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 6 of 22 Biopesticides Registration Action Document

II

. ACTIVE INGREDIENT OVERVIEW

Biological Name: Bacteriophage of Clavibacter michiganensis subsp. michiganensis

OPP Chemical Code: 228983

Type of Pesticide: Microbial Pesticide

– Bactericide

See Appendix B for specific information ( e.g., use sites, application rates, methods of application, formulation types, and target pests) regarding t he pesticide product containing this active ingredient.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 7 of 22 Biopesticides Registration Action Document

III. REGULATORY BACKGROUND

A

. Application for Pesticide Registration

On March 23, 2009

, OmniLytics, Inc. (address: 9100 South 500 West, Sandy, Utah 84070 )

submitted an application to register an end

- use pesticide product, AgriPhage CMM (EPA File Symbol 67986

- A )

, under FIFRA section 3. On M arch 10, 2010

, EPA announced receipt of this application to register a pesticide product containing a new active ingredient ( 75 Federal Register (FR) 11175 ) and opened a 3 0

- day public comment period p ursuant to the provisions of FIFRA section 3(c)(4). No comments were received following this publication

.

B. North American Free Trade Agreement Joint Review

B acteriophage of Clavibacter michiganensis subsp. michiganensis was the subject of a North American Free Trade Agreement joint registration review conducted by the Environmental Protection Agency Office of Pesticide Programs and the Health Canada Pest Management Regulatory Agency (PMRA) . The PMRA “Proposed Registrati on Decision,” a consultation document recommending full registration of bacteriophage of Clavibacter michiganensis subsp. michiganensis , is being drafted , prior to a 45

- day public comment period.

C

. Food Tolerance Exemption

Concurrent with its registration application and under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(d), OmniLytics, Inc. submitted a petition to establish an exemption from the requirement of a tolerance for bacteriophage of Clavibacter michiganensis subsp.

michi ganensis (Pesticide Petition (PP) 9E7552 ). In the Federal Register of September 23, 2009 ( 7 4 FR 48556 ), EPA announced that Interregional Research Project Number 4 (IR

- 4), Rutgers University, on behalf of OmniLytics, Inc., proposed to establish an exemption from the requirement of a tolerance for residues of the microbial pesticide

, bacteriophage of Clavibacter michiganensis su bsp. michiganensis

, in or on tomato and opened a 30

- day comment period. No comments were received following this publication

.

IV. RISK ASSESSMENT

In the Federal Register of October 26, 2007, EPA issued a Final Rule on the data requirements to

support registration of microbial pesticides and updated the definition for microbial pesticides ( 72 FR 61002 ). The rule became effective on December 26, 2007. The data and information evaluated for this BRAD were considered in light of these requirements.

The classifications that are found for each data submission are assigned by EPA science

reviewers and are an indication of the usefulness of the information contained in the documents for risk assessment. A rating of “ acceptable ” indicates the study is scientifically sound and is

useful for risk assessment. A “ supplemental ” rating indicates the data provide some information that can be useful for risk assessment. The studies may have c ertain aspects determined not to be scientifically acceptable (“ supplemental : upgradeable ”). If a study is rated as “ supplemental : upgradeable ,” EPA always provides an indication of what is lacking or what can be provided to change the rating to “ acceptabl e .” If there is simply a “ supplemental ” rating, the reviewer will

often state that t he study is not required by 40 C FR P art 158. Both “ acceptable ” and

“ supplemental ” studies may be used in the risk assessment process as appropriate. AnBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 8 of 22 Biopesticides Registration Action Document

“ unacceptable ” ratin g indicates that new data must be submitted.

For the acu te toxicity data requirements, Toxicity C ategories are assigned based on the hazard(s)

identified from studies and/or other information submitted to EPA in support of a pesticide registration. The ac tive ingredient or particular product is classified into Toxicity Category I, II, III, or IV, where Toxicity Category I indicates the highest toxicity and Toxicity Category IV indicates the lowest toxicity ( 40 CFR § 156.62 )

.

A

. Product Analysis Assessment ( 40 CFR § 158.2120 )

A ll product analysis data requirements for bacteriophage of Clavibacter michigane nsis subsp. michiganensis have been fulfilled ( Master Record Identification Numbers ( MRID Nos

. ) 477204

- 01, 480536

- 01 and 483831

- 01). Refer to Tables 1 and 2 in Appendix A for a brief summary of

the data requirements.

B

. Human Health Assessment ( 40 CFR § 158.2140 )

1

. Toxicity

All toxicology data requirements for bact eriophage of Clavibacter michiganensis subsp. michiganensis have been fulfilled

. Acceptable Tier I mammalian toxicology data waiver

rationales support registration of bacteriophage of Clavibacter michiganensis subsp. michiganensis pesticide product

. Furthermore, Tier II and Tier III studies were not required for bacteriophage of Clavibacter michiganensis subsp. michiganensis based on data waiver rationales provided for Tier I toxicity/pathogenicity studies. Refer to Table 3 in Appendix A for a brief summary of the data requirements.

a. Acute Toxicity/Pathogenicity

– Tier I

The applicant included a thorough literature review and set of rationale s to waive requirements for toxicology, pathogenicity, infectivity

, and irritation testing for bacteriophage of Clavibacter michiganensis subsp. michiganensis ( MRID No

. 477204

- 02). The s ubmitted literature established that bacteriophage have been used historically and through modern times in lieu of

, or to assist the action of

, antibiotics. Clinical uses encompass all manner of administration from injection/intravenous and surgical wound applications to topical and ingestible preparations. They are also used to test normal and variously impaired human immune system function. There have been no reports of adverse effects from such administrations of bacteriophage in the published literature or in cases using controlled scientific studies. Also submitted were literature citations showing that bacteriopha ge are present in high numbers in the environment

, including

in non

- polluted waters up to 10 10 PFU/L and up to 10 5 PFU/L in treated drinking water

. EPA granted the data waiver requests based on submitted literature and rationale

.

b. Acute Toxicology and Subchronic Toxicity/Pathogenicity

– Tier II; Reproductive Fertility Effects, Carcinogenicity, Immunotoxicity, and Infectivity/Pathogenicity Analysis

– Tier III

Tier II and Tier III studies were not required for bacteriophage of Clavibacter mich iganensis subsp. michiganensis based on the lack of acute toxicity/pathogenicity in the Tier I data waiverBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 9 of 22 Biopesticides Registration Action Document

rationale s, and a Toxicity Category IV has been determined for bacteriophage of Clavibacter michiganensis subsp. michiganensis product Agriphage Cmm.

c. Endocrine Disruptors

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily r equired determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to ide ntify any adverse endocrine

- related effects caused by the substance, and establish a quantitative relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

B acteriophage of Clavibacter michiganensis subsp. michiganensis is not among the group of 58 pesticide active ingredients on the initial list to b e screened under the EDSP. Under FFDCA section 408(p), EPA must screen all pesticide chemicals. Accordingly, EPA anticipates issuing

future EDSP orders/data call

- ins for all pesticide active ingredients.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

2

. F ederal Food, Drug, and Cosmetic Act ( FFDCA ) Consid erations

Section 408(c)(2)(A)(i) of FFDCA allows EPA to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the exemption is “safe.” Section 408(c)(2)(A )(ii) of FFDCA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for

which there is reliable information.” This includes exposure through drinking water and in residential settings but does not include occupational exposure. Pursuant to section 408(c)(2)(B) of FFDCA, in establishing or maintaining in effect an exemption from the requirement of a

t olerance, EPA must take into account the factors set forth in section 408(b)(2)(C) of FFDCA, which require EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance exemption and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue....” Additionally, section 408(b)(2)(D) of FFDCA requires that

EPA consider “available information conce rning the cumulative effects of [a particularBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 10 of 22 Biopesticides Registration Action Document

pesticide's]

. . . residues and other substances that have a common mechanism of toxicity.”

EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, EPA det ermines the toxicity of pesticides. Second, EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings.

Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the available scientific data and other relevant information and considered its validity, completeness, and reliability and the relationship of this information to human risk. EPA has also considered available information concerning the varia bility of the sensitivities of major identifiable subgroups of consumers, including infants and children.

Based on the acute toxicity/pathogenicity information discussed previously and presented in

Table 3 in Appendix A , t he data required for a FFDCA risk assessment for b acteriophage of Clavibacter michiganensis subsp. michiganensis have been fulfilled

.

a. Aggregate Exposure

In examining aggregate exposure, section 408 of FFDCA directs EPA to consider available

information concerning exposures from the pesticide residue in food and all other nonoccupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor

us es).

Food Exposure and Risk Characterization : All bacterio phages, including those at issue in this action, are similar in nature in that they are host

- specific, attacking only bacteria

. Published

scientific literature submitted by the registrant, and othe r publically available literature indicate that humans are exposed to bacterio phages daily, and are commonly found in humans , with no known adverse effects

. Indeed, humans and other animals routinely consume bacteriophages when they eat food such as meat and cheese

. Several studies have suggested that 100% of the ground beef and chicken meat sold at retail contain various levels of various bacteriophage

. For example, bacteriophage s were recovered from 100% of examined fresh chicken and pork sausage samples and from 33% of delicatessen meat samples analyzed

. The levels ranged from

3.3

- 4.4x10 10 PFU/100g of fresh chicken, up to 3.5x10 10 PFU/100g of fresh pork, and up to

2.7x10 10 PFU/100g of roast turkey samples

. Bacteriophage s recovered were typically in the range of 10 1

- 10 5 PFU/100 g meats and up to 10 7 PFU/100 g in cheese

. Based on the above and the fact that bacteriophage s are host

- specific ; these organisms are not known to pose any human

health effects

. Throughout the litera ture cited by the registrant and other publically available literature, there have been no known adverse effects to humans ever reported

. Accordingly , the Agency concludes that when Clavibacter michiganensis subsp. m ichiganensis specific bacteriophages are used according to the manner intended, there is a reasonable certainty that no harm will result to humans from all anticipated dietary exposures (through food) to any residues resulting from such use. Bacteriophage s are ubiquitous in the environment ; therefore, humans and other mammals are regularly exposed to bacteriophage s with no adverse effects reported in the published scientific literature. A literature review show ed bacteriophage s are already commonly consumed by humans via various foods. Bacte riophage may contain genes for substances that may be toxic or associated with pathogenicity, however, they are incapable of producin g toxins outside host bacteria. Bacteriophages consist solely of genetic material encapsulated in a protein envelope and do not have the metabolic processes required for toxinBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 11 of 22 Biopesticides Registration Action Document

production.

Drinking Water Risk Characterization : Bacteriophage of Clavibacter michiganensis subsp. michiganensis are not intended for use in drinking water, nor are the approved uses likely to

result i n these bacteriophages reaching surface water or ground water that might be used as drinking water

. Furthermore, in the unlikely event that bacteriophage of Clavibacter michiganensis subsp. michiganensis do reach water consumed by humans, for the many reas ons enumerated above, the Agency concludes that when bacteriophage of Clavibacter michiganensis subsp. michiganensis are used in the manner intended, there is a reasonable certainty that no harm will result to humans from all anticipated dietary exposures (through water) to any residues resulting from such use. Exposure of humans to bacteriophage of Clavibacter michiganensis subsp. michiganensis in drinking water due to its proposed uses as a pesticide is not likely, as the proposed use patterns and use sit es do not include direct application to aquatic environments, thereby limiting contact with surface water. If oral exposure should occur through consumed drinking water, however, EPA concludes that there is a reasonable certainty that no harm will

result f rom exposure to such residues because of the lack of toxicity, infectivity, and or pathogenicity in the previously described toxicological studies (see section IV(B)(1)(a) and

Table 3 in Appendix A )

.

Nonoccupational, Re sidential Risk Characterization : Since bacteriophage of Clavibacter michiganensis subsp. michiganensis are host specific, the potential for nonoccupational, nondietary exposures (i.e., dermal and inhalation exposures) to these bacteriophages by the general populati on, including infants and children, is highly unlikely

. Moreover, the general population, including infants and children, are exposed to bacteriophage s daily in food and drinking water with no known adverse effects ever being reported

. Additionally, all pr oposed uses occur in distinctly agricultural or commercial settings, and there are no proposed uses for

residential areas

. The Agency concludes , therefore, that in the unlikely event there is nonoccupational, nondietary exposure to those specific bacteriophages , such exposures would pose no risks to the general population, including infants and children. Nonoccupational exposure is not expected for bacteriophage of Clavibacter michiganensis subsp. michiganensis as all proposed uses occur in distinc tly agricultural or commercial settings, and there are no proposed uses for residential areas.

b. Cumulative Effects from Substances with a Common Mechanism of Toxicity

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establi sh, modify, or revoke a tolerance exemption, EPA consider “available information concerning the cumulative effects of [a particular pesticide’s]

... residues and other substances that have a common mechanism of toxicity.”

EPA has not found bacteriophage of Clavibacter michiganensis subsp. michiganensis to share a common mechanism of toxicity with any other substances, and each bacteriophage isolate added to the AgriPhage CMM library is tested for ability to infect closely related bacteria. Inability to

infec t bacteria outside the genus Claviba c ter is important to prevent passage of toxic or pathogenic genes to other bacteria by the bacteriophage

. The registrant has in place limitations for bacteriophage hosts, namely use of only non

- toxigenic Clavibacter mich iganensis subspecies michiganensis (an obligate plant associated bacterium infecting t omatoes) to produce phage, and use of only lytic (and not lysogenic) 1 bacteriophage, giving further assurance that toxin production would not even be carried as a trait b y these bacteriophage. For the purposes of thisBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 12 of 22 Biopesticides Registration Action Document

tolerance action, therefore, EPA has assumed that bacteriophage Clavibacter michiganensis

_______________________________________________
1 Lytic bacteriphages only multiply and kill the ir host bacterium by cell lysis at the end of their life cycle. L ysogenic bacteriophages can multiply via the lytic cycle, but usually enter a quiescent state in the host bacterium, and integrate their DNA into the host’s DNA. The host harboring the bacteriophage DNA is not affected by the presence of the bacteriophage’s DNA. When the infected bacterium undergoes normal cell division, t he bacteriophage genes are replicated along with the host’ s, and are passed on to the bacterial “ daughter ” cells. If the bacteriophage begins to replicate, and brings into its DNA any genes encoding toxins or pathogens, the lysogenic

- type bacteriophage can transmit those genes to other similar host bacteria that otherwise would not produce the toxins or pathogenic substances.

subsp. michiganen sis does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

c. Determination of Safety for the U.S. Population, Infants and Children

FFDCA section 408(b)(2)(C) provides that EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and children of the residues

and other subst ances with a common mechanism of toxicity. In addition, FFDCA section 408(b)(2)(C) provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal to xicity and the completeness of the database on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA Safety Factor. In apply ing this provision, EPA either retains the default value of 10X or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor. Based on the acute toxicity and pathogenicity data waiver rationales summarized in section IV(B)(1)(a) and Table 3 in Appendix A

, EPA concludes that there is a reasonable certainty that

no harm will result to the U.S. population, including infants and children, from aggregate exposure to the resid ues of bacteriophage of Clavibacter michiganensis subsp. michiganensis

. This includes all anticipated dietary exposures and all other exposures for which there is reliable

information. EPA has arrived at this conclusion because the information available on bacteriophage of Clavibacter michiganensis subsp. michiganensis do es not demonstrate toxic, pathogenic, and/ or infective potential to mammals. Thus, there are no threshold effects of concern and, as a result, the provision requiring an additi onal margin of safety does not apply.

3

. Occupational Exposure and Risk Characterization

Handler exposure to bacteriophage of Clavibacter michiganensis subsp. michiganensis is not expected to pose any undue risk , but appropriate personal protective equipment and precautionary statements are required on pesticide product labels to mitigate any potential risks to pesticide handlers due to prolonged or numerous exposures. Handlers applying bacteriophage

of Clavibacter mi chiganensis subsp. michiganensis end

- use products in commercial and agricultural settings must wear a long

- sleeved shirt, long pants, socks, shoes, waterproof gloves, and a dust/mist filtering respirator meeting NIOSH standards of at least N

- 95, R

- 95, or P

- 95. Additional PPE, other than the standard described above, may be required on a product

- specific

basis.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 13 of 22 Biopesticides Registration Action Document

4

. Human Health Risk Characterization

EPA considered human exposure to bacteriophage of Clavibacter michiganensis subsp. michiganensis in light of the standard for registration in FIFRA and the relevant safety factors in

FFDCA. A determination has been made that no unreasonable adverse effects to the U.S. population in general, and to infants and children in particu lar, will result when bacteriophage of Clavibacter michiganensis subsp. michiganensis pesticide products are used in accordance with

EPA

- approved labeling.

C

. Environmental Assessment ( 40 CFR § 158.2150 )

The data waiver rationales , submitted by the applicant to support the pesticide products containing bacteriophage of Clavibacter michiganensis subsp. michiganensis

, are sufficient to fulfill the Tier I nontarget organism data requirements and for risk assessment purposes. Further testing of nontarget organisms at higher tier levels (i.e., Tiers II, III, and IV) is not required for the current uses and application methods . EPA has performed an environmental risk assessment

based on the data waiver rationales provided by the applicant and has dete rmined that the proposed use of bacteriophage of Clavibacter michiganensis subsp. michiganensis does not pose significant risk to nontarget organisms when used according to label directions.

For a comprehensive summary of the generic data requirements described in sections IV(C)(1),

refer to Table 4 in Appendix A

.

1

. Ecological Exposure and Risk Characterization

Since bacteriophage are not capable of infecting eukaryotic cells, it is reasonable to expect those bacteriophage are also not capable of causing infection in eukaryotic organisms. Nontarget

bacteria are unl ikely to be adversely affected

, since individual bacteriophage typically have a limited host range. Additionally, the applicant has a testing program to ensure pesticidal bacteriophage do not have a broad host range. Bacteriophage s are ubiquitous in the en vironment,

and nontarget organisms are regularly exposed directly to bacteriophage with no adverse effects reported in the published scientific literature. Bacteriophage s may contain genes for substances that may be toxic to nontarget organisms ; however, t hey are incapable of producing toxins

outside of their host bacteria

, since they consist solely of genetic material encapsulated in a protein envelope and do not have the metabolic processes required for toxin production. The applicant has in place limitat ions for the bacterial hosts, namely use of only nontoxigenic Clavibacter michiganensis to produce the bacterio phage and use of only lytic (and not lysogenic) bacteriophage, giving further assurance that toxin production would not even be carried as a trait by these bacteriophage. Based on the narrow host range of bacteriophage of Clavibacter michiganensis subsp. m ichiganensis to certain bacterial species , as well as the biological properties of bacteriophage in general, they are not expected to pose any hazard to nontarget terrestrial or aquatic organisms.

2

. Environmental Fate Data

As t he information provided f or the curre nt uses and application methods is sufficient to both satisfy the Tier I nontarget organism data requirements and for nontarget organism risk

asse ssment for bacteriophage of Clavibacter michiganensis subsp. michiganensis , f urther testing at hig her tier levels (i.e., Tiers II, III, and IV) is not required

.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 14 of 22 Biopesticides Registration Action Document

3

. Threatened and Endangered Species Assessment

EPA has determined that adverse effects will not occur to nontarget organisms as a result of the proposed labeled applications of bacteriophage of Clavibacter michiganensis subsp. michiganensis

.

Since EPA has determined that no effects are anticipated for any nontarget species exposed to bacteriophage of Clavibacter michiganensis subsp. michiganensis as a result of the proposed

lab eled applications, effects to federally listed

, threatened and endangered species and their designated critical habitats are also not expected. Therefore, a “No Effect” determination is made for direct and indirect effects to listed species and their desig nated critical habitats resulting from the proposed uses of bacteriophage of Clavibacter michiganensis subsp. michiganensis , as labeled.

V

. ENVIRONMENTAL JUSTICE

EPA seeks to achieve environmental justice

— the fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income

— with respect to the development, implementation, and enforcement of environmental laws, regulations , and policies. Fair treatment means that no group of people, including racial, ethnic, or socioeconomic groups, should bear a disproportionate share of the negative environmental consequences resulting from industrial, municipal, and commercial operations or the execution of federal, state, local, and tribal environmental programs and policies. Meaningful involvement means that (1) potentially affected community residents have an appropriate opportunity to participate in decisions about a proposed activity that will affect their environment and/or health; (2) the public’s contribution can influence the regulatory agency’s decision; (3) the concerns of all participants involved will

be considered in the decision

- making process; and (4) the decision

- makers se ek out and facilitate the involvement of those potentially affected. EPA has this goal for all communities and persons

across the United States.

To help address potential environmental justice issues, EPA seeks information on any groups or segments of th e population who, as a result their location, cultural practices, or other factors, may have atypical, unusually high exposure to bacteriophage of Clavibacter michiganensis subsp. michiganensis , compared to the general population. Please comment if you are aware of any subpopulations that may have atypical, unusually high exposure compared to the general population.

For additional information regarding environmental justice issues, please visit EPA’s web site at http://www.epa.gov/compliance/environmentaljustice/index.html

.

V I

. RISK MANAGEMENT DECISION

Pursuant to Section 3(c )(5) of FIFRA, EPA may register a pesticide provided that all the following determinations are made:

(1) Its composition is such as to warrant the proposed claims for it; (2) Its labeling and other material required to be submitted comply with the requirements of FIFRA;Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 15 of 22 Biopesticides Registration Action Document

(3) It will perform its intended function without unreasonable adverse effects on the

envi ronment; AND (4) When used in accordance with widespread and commonly recognized practice, it will not generally cause unreasonable adverse effects on the environment.

With respect t o criterion 1, the proposed pesticide product containing bacteriophage of Clavibacter michiganensis subsp. michiganensis has well

- known properties. EPA has no knowledge that would contradict the claims made on the AgriPhage CMM label , and the pesticide product is not expected to cause unreasonable adverse effects on the environ ment when used according to the label instructions. Regarding c riterion 2

, the current product label, as well as the data and information presented in this document , comply with the requirements of FIFRA

. It is believed that bacteriophage Clavibacter michi ganensis subsp. michiganensis pesticide product will not cause any unreasonable adverse effects on the environment, and AgriPhage

CMM is likely to provide protection against bacterial canker disease on tomatoes as claimed,

thus satisfying criterion 3. Crit erion 4 is satisfied in that bacteriophage Clavibacter michiganensis subsp. michiganensis pesticide product is not expected to cause unreasonable adverse effects when used according to label instructions. AgriPhage CMM

, containing bacteriophage of Clavibacter michiganensis subsp. michiganensis as a new active ingredient, is eligible for registration under FIFRA section 3(c)(5) for the labeled uses.

V I I

. ACTIONS REQUIRED BY THE REGISTRANT

A

. Final Printed Labeling

Before releasing AgriPhage CMM for shipment, the registrant is required to provide appropriate final printed labeling to EPA

.

B

. Terms of Registration

EPA has determined the following t erms must be met for the registration of bacteriophage of Clavibacter michiganensis subsp. michiganensis as a new microbial active ingredient

.

1. Deposition of a sample of bacteriophage of Clavibacter michiganensis subsp. michiganensis into a nationally recognized culture collection (40 CFR 158.2120). The sample should be deposited under a maint enance agreement so that there is no chance the culture collection will discard it. The sample must remain on deposit as long as the registration is maintained. The Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the P urposes of Patent Procedure (available from the World Intellectual Property Organization at http://www.wipo.int ) provides information on what constitutes a “recognized” cu lture collection that would provide assurance for maintenance of a culture deposit.

2. A new Storage Stability Study (OCSPP 830.6317) of bacteriophage of Clavibacter michiganensis subsp. michiganensis must be submitted within one (1) year of registration

to support the labeled via bility claim of the product. The original storage stability study submitted was found to be ACCEPTABLE, but a substantial decline of PFU/mL occurred

after th e first 120 days of the study. The new study will verify the viability claim of the product.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 16 of 22 Biopesticides Registration Action Document

C

. Reporting of Adverse Effects and Hypersensitivity Incidents

Notwithstanding the information stated in the previous sections, it should be clearly understood that certain, specific data are required to be reported to EPA as a requirement for maintaining the federal registration for a pesticide product. A brief summary of these types of data are described

below.

Reports of all incidents of adverse effects to the environment must be submitted to EPA under the provisions stated in FIFRA section 6(a)(2). Additionally, all incidents of hypersensitivity (including both suspected and confirmed incidents) must be reported to EPA under the provisions of 40 CFR § 158.2140(d).Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 17 of 22 Biopesticides Registration Action Document

VIII

. GLOSSARY OF ACRONYMS AND ABBREVIATIONS

BPPD Biopest icides and Pollution Prevention Division

BRAD Biopesticides Registration Action Document

CFR Code of Federal Regulations

cP centipoise

EDSP Endocrine Disruptor Screening Program

EP end

- use product

EPA Environmental Protection Agency (the “Agency”)

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act

FR Federal Register g/mL gram per milliliter

MP manufacturing

- use product

MRID No. Master Record Identification Number

NIOSH National Institute for Occupational Safety and Health

OCSPP Office of Chemical Safety and Pollution Prevention

OPP Office of Pesticide Programs

PC Code Pesticide Chemical Code

PFU Plaque Forming Unit

PP Pesticide Petition

PPE personal protective equipment

TGAI technical grade of the active ingredientBacteriophage of Clavibacter michiganensis subsp. michiganensis Page 18 of 22 Biopesticides Registration Action Document

IX

. BIBLIOGRAPHY

A

. Studies Submitted to Support the AgriPhage CMM Pesticide Product Registration

M RID No. Study Title

47720400 Interregional Research Project No. 4 (2009) Submission of Product Chemistry, Toxicity, and Residue Data in Support of the Application for Registration of Agriphage CMM, and the Petition for Tolerance of Bacteriophage of Clavibacter michiganensis subsp. michiganensis for

Use on Tomatoes. Transmittal of 3 Studies.

47720401 Walbeck, A. (2009) Product Chemistry: Bacteriophage of Clavibacter michiganensis subsp. michiganensis

- AgriPhage CMM. Project Number: 0430B. Unpublished study prepared by OmniLytics, Inc. 295 p.

47720402 Walbeck, A.; Braverman, M. (2009) Rationale for Waiver of Toxicity and Residue Data Requirements: Bacteriophage of Clavibacter michiganensis subsp. michiganensis

- AgriPhage CMM. Project Number: 0430B. Unpublished study prepared by OmniLytics, Inc. 175 p.

47720403 Wal beck, A.; Braverman, M. (2009) Rationale for Waiver of Non Target Organism Testing Requirements: Bacteriophage of Clavibacter michiganensis subsp. michiganensis

- AgriPhage CMM. Project Number: 0430B. Unpublished study prepared by OmniLytics, Inc. 169 p.

48053600 Omnilytics, Inc. (2010) Submission of Product Chemistry Data in Support of the Application for Registration of AgriPhage CMM. Transmittal of 1 Study.

48053601 Blum, K. (2010) Product Analysis Test Guidelines: AgriPhage

- CMM. Project Number: IR/4/P R/0430B. Unpublished study prepared by Omnilytics, Inc. 335 p.

48383100 OmniLytics, Inc. (2011) Submission of Product Chemistry Data in Support of the Application for Registration of AgriPhage CMM. Transmittal of 1 Study.

48383101 Blum, K. (2010) Product Analysis Test Guidelines: AgriPhage

- CMM. Project Number: IR/4/PR/430B. Unpublished study prepared by OmniLytics, Inc. 327 p.

B

. Environmental Protection Agency and Pest Management Regulatory Agency Risk

Assessment Memoranda

PMRA. 2011a. Avian Oral; Avian Pulmonary, Inhalation or Injection; Fish: Freshwater; Arthropods: Terrestrial; Arthropods: Aquatic; Non

- Arthropod invertebrates: Terrestrial;

Non

- Arthropod invertebrates: Aquatic; Plants: Terrestrial; Plants: Aquatic ─ Waiver Request Sub. No

. 2009

- 1066/ OmniLytics Inc. [OMT] Lytic bacteriophage of Clavibacter michiganensis subsp. michiganensis [TOM] . Data Evaluation Record from J. Ptasinski signed March 25, 2010 and J.V. Gagliardi signed June 2, 2011.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 19 of 22 Biopesticides Registration Action Document

U.S. EPA. 20 11 b

. Bacteriophage of Cla vibacter michiganensis subsp. michiganensis

– AgriPhage CMM

. Memorandum from J.V. Gagliardi , Ph.D. and J

. Ptasinski to A

. Gross

dated May 25 , 2011

.

U.S. EPA. 2011c

. Human Health and Environmental Risk Assessment of Bacteriophage of

Clavibacter michiganensis subsp. michiganensis (PC Code: 228983 )

. Memorandum from J.V. Gagliardi to A. Gross dated Ju n e 30 , 2011.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 20 of 22 Biopesticides Registration Action Document

A PPENDIX A

. MICROBIAL PESTICIDES DATA REQUIREMENTS (40 CFR PART 158

– SUBPART V )

TABLE 1

. Product Analysis Data Requirements for Bacteriophage of Clavibacter michiganensis subsp. michiganensis

, AgriPhage CMM (40 CFR § 158.2 120 )

OCSPP

Guideline

Number Data Requirement Results MRID No.

885.1100 Product Identity Submitted data fulfill the requirement for product identity. 477204

- 01

480536

- 01

483831

- 01

885.1200 Manufacturing Process Submitted data fulfill the requirement for manufacturing

process. 477204

- 01

480536

- 01

483831

- 01 Not applicable Deposition of a Sample in a Nationally Recognized Culture

Collection Not applicable

- Enforcement Analytical Method was conducted in lieu of Depositing a Sample in a Nationally Recognized Culture Collection

885.1300 Discussion of Formation

of Unintentional Ingredients Submitted data fulfill the requirement for discussion of formation of unintentional ingredients. 477204

- 01

480536

- 01

483831

- 01

885.1400 Analysis of Samples Submitted data fulfill the requirement for analysis of samples. 477204

- 01

480536

- 01

483831

- 01

885.1500 Certification of Limits Limits listed on the confidential statement of formula are adequate/acceptable.

Additional Studies

830.1800 Enforcement Analytical

Method Submitted data fulfill the requirement for an enforcement analytical method. 477204

- 01

480536

- 01

483831

- 01

TABLE 2

. Physical and Chemical Characteristics for Bacteriophage of Clavibacter michiganensis subsp. michiganensis

, AgriPhage CMM (40 CFR § 158.2120)

OCSPP

Guideline

Number Data Requirement Results MRID No.

830.6302 Color Golden Yellow 477204

- 01

830.6303 Physical State Liquid 477204

- 01

830.6304 Odor None to slight 477204

- 01

830.6313 Stability to Normal and

Elevated Temperatures, Metals,

and Metal Ions Not applicable 477204

- 01

830.6317 Storage Stability At least one year at 4°C 477204

- 01

830.6319 Miscibility Completely miscible in water 477204

- 01

830.6320 Corrosion

Characteristics Not corrosive 477204

- 01

830.7000 pH 5.3

- 6.2 477204

- 01

830.7100 Viscosity 0.90 cP at 21°C 477204

- 01

830.7300 Density/Relative Density/Bulk Density

(Specific Gravity) 1.002

- 1.006 g/mL 477204

- 01Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 21 of 22 Biopesticides Registration Action Document

T ABLE 3

. Toxicology Data Requirements for AgriPhage CMM (40 CFR § 158.2140)

OCSPP Guideline

Number Data Requirement Results MRID No.

Tier I

885.3050 Acute Oral Toxicity/Pathogenicity Waived given that bacteriophage are viruses that only infect specific bacteria. Bacteriophage are present in high numbers in

the environment and non

- polluted waters and there have been no reports of adverse effects from exposure. Classification: Acceptable 477204

- 02 885.3150 Acute Pulmonary Toxicity/Pathogenicity

885.3200 Acute Injection Toxicity/Pathogenicity (Intravenous)

885.3400 Hypersensitivity

Incidents No hypersensitivity incidents, including immediate

- type or delayed

- type reactions of humans and domestic animals that

occurred during research, development, or testing of the AgriPhage CMM , were reported by the applicant. Any future hypersensitivity incidents must be reported per OCSPP Guideline

885.3400.

885.3500 Cell Culture Waived given that bacteriophage are viruses that only infect specific bacteria. Bacteriophage are present in high numbers in

the environment and non

- polluted waters and there have been no reports of adverse effects from exposure

. Classification: Acceptable 477204

- 02 870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Acute Eye Irritation

Tiers II and III Not required for bacteriophage of Clavibacter michiganensis subsp. michiganensis based on the lack of acute toxicity/pathogenicity in the Tier I data waiver rationale

.

TABLE 4

. Nontarget Organism Toxicity and Environmental Fate Data Requirements for Bacteriophage of Clavibacter michiganensis subsp. michiganensis

, AgriPhage CMM (40 CFR § 158.2150)

OCSPP Guideline

Number Data Requirement Results MRID No.

Tier I

885.4050 Avian Oral Toxicity
Waived based on the fact that, since bacteriophage are not capable of infecting eukaryotic cells, it is reasonable to expect that bacteriophage are also not capable of causing infection in eukaryotic organisms. Nontarget bacteria are unlikely to be adverse ly affected since individual bacteriopha g e typically

have a limited host range amongst bacteria and it is uncommon for a bacteriophage to be able to infect outside of a bacterial species. Additionally, the registrant has a testing program to ensure pestici dal bacteriophage do not have a broad host range. Classification: Acceptable 477204

- 03 885.4100 Avian Inhalation Toxicity/Pathogenicity

885.4150 Wild Mammal Toxicity/Pathogenicity

885.4200 Freshwater Fish Toxicity/Pathogenicity

885.4240 Freshwater Invertebrate Toxicity/Pathogenicity

885.4280 Estuarine/Marine Fish and Invertebrate Testing

885.4300 Nontarget Plant Testing

885.4340 Nontarget Insect Testing

885.4380 Honey Bee Testing Tiers II, III, and IV Not required for bacteriophage of Clavibacter michiganensis subsp. michiganensis based on the current uses and application

methods.Bacteriophage of Clavibacter michiganensis subsp. michiganensis Page 22 of 22 Biopesticides Registration Action Document

APPENDIX B

. PESTICIDE PRODUCTS

EPA File Symbol Registration

Name Percentage

Active Ingredient Formulation Type Use Site(s) Method(s) of Application Application

Rate Target

Pest

67986

- A AgriPhage

CMM 0.0 00 5% End Use Tomato Seed ling

Treatment (4 leaf stage) (Foliar Spray

or Hydroponic) 1 pint of AgriPhage

CMM/ 9600 sq. ft. greenhouse

space Bacterial

Canker

Disease

Hydroponic

Greenhouse

Treatment 2 to 4 quarts of Agriphage

CMM /100 gallons of

water per acre

Field

Treatment (Foliar Spray) 1

- 2 pints of AgriPhage

CMM/100 gallons of

water/acre for

field applications